Background

Periventricular leukomalacia (PVL) is the most common ischemic brain injury in premature infants. The ischemia occurs in the border zone at the end of arterial vascular distributions. The ischemia of periventricular leukomalacia occurs in the white matter adjacent to the lateral ventricles. The traditional diagnostic hallmarks of periventricular leukomalacia are periventricular echodensities or cysts detected by cranial ultrasonography, as shown below. More recently MRI studies have demonstrated a relatively common diffuse non-cystic form of periventricular leukomalacia in premature infants. Diagnosing periventricular leukomalacia is important because a significant percentage of surviving premature infants develop cerebral palsy (CP), intellectual impairment, or visual disturbances.

Pathophysiology

The pathophysiology of periventricular leukomalacia is a complex process. Periventricular leukomalacia occurs because of ischemia induced injury to oligodendrocytes in the periventricular area of the developing brain. Cytokine-induced damage following maternal or fetal infection may play a role.

Periventricular leukomalacia is a white matter lesion in premature infants that results from hypotension, ischemia, and coagulation necrosis at the border or watershed zones of deep penetrating arteries of the middle cerebral artery.

Several factors related to vascular development make the periventricular region of the preterm brain uniquely sensitive to ischemic injury. First, early in development, the deep penetrating arteries that supply the watershed zone of the periventricular white matter lack the vascular anastomoses that help maintain perfusion during periods of hypotension. As the fetus matures, the number of anastomoses between the deep penetrating arteries increases, and the periventricular white matter becomes less susceptible to small decreases in blood pressure.

The second vascular developmental factor that plays a role in periventricular leukomalacia is related to cerebral autoregulation. Premature infants have impaired cerebrovascular blood flow autoregulation, increasing their susceptibility to periventricular leukomalacia and intracranial hemorrhage (ICH). Decreased blood flow affects the white matter at the superolateral borders of the lateral ventricles. The site of injury affects the descending corticospinal tracts, visual radiations, and acoustic radiations.

Maternal infection, placental inflammation, and vasculitis are also important in the pathogenesis of periventricular leukomalacia. A link between maternal infection, preterm birth, and CNS injury has been established by epidemiological studies.
[1, 2] A role for infection and cytokine-induced injury in periventricular leukomalacia is strengthened by studies that demonstrate the presence of tumor necrosis factor in periventricular leukomalacia lesions
[3] and in the cerebrospinal fluid (CSF) of infants with cerebral white matter injury.
[4]

After the initial insult, either ischemia or inflammation, injury to the immature premyelinating oligodendrocytes occurs by either free radical attack or by excitotoxicity. The preterm infant is particularly sensitive to oxygen free radical attack because of delayed development of superoxide dismutase and catalase.
[5]

In a 2014 report, Inomata et al suggested that combined elevations in serum levels of interleukin (IL) 6 and C-reactive protein (CRP) at birth are predictive of white matter injury in preterm infants with a fetal inflammatory response (FIR).
[6]

Injury to the premyelinating oligodendrocytes results in astrogliosis and microgliosis. This results in a deficit of mature, myelin-producing oligodendrocytes, which leads to cerebral hypomyelination.
[7]

Premature infants on mechanical ventilation may develop hypocarbia. Several studies have linked hypocarbia, particularly in the first few days of life, with the development of periventricular leukomalacia.
[8, 9] Cumulative exposure during the first 7 days of life has been shown to independently increase the risk of periventricular leukomalacia in low birth weight infants.
[10, 11]

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Epidemiology

Frequency

United States

The incidence of periventricular leukomalacia ranges from 4-26% in premature infants in neonatal intensive care units (NICUs). The incidence of periventricular leukomalacia is much higher in reports from autopsy studies of premature infants. As many as 75% of premature infants have evidence of periventricular leukomalacia on postmortem examination.

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Prognosis

Infants with periventricular leukomalacia are at risk for development of neurodevelopmental deficits. Mild periventricular leukomalacia is often associated with spastic diplegia. Severe periventricular leukomalacia is associated with quadriplegia. Severe periventricular leukomalacia is also associated with a higher incidence of intelligence deficiencies and visual disturbances.

Morbidity/mortality

Periventricular leukomalacia occurs most commonly in premature infants born at less than 32 weeks' gestation. Many infants with periventricular leukomalacia later develop signs of CP. Spastic diplegia is the most common form of CP following mild periventricular leukomalacia. Severe periventricular leukomalacia is frequently associated with quadriplegia.

Varying degrees of intellectual impairment, developmental impairment, or both have been reported in association with periventricular leukomalacia. Fixation difficulties, nystagmus, strabismus, and blindness have been associated with periventricular leukomalacia. Some cases of visual dysfunction in association with periventricular leukomalacia occur in the absence of retinopathy of prematurity, suggesting damage to optic radiations as causation.

Liao SL, Lai SH, Chou YH, Kuo CY. Effect of hypocapnia in the first three days of life on the subsequent development of periventricular leukomalacia in premature infants. Acta Paediatr Taiwan. 2001 Mar-Apr. 42(2):90-3. [Medline].

Cranial ultrasound, coronal view, in 1-week-old premature infant. The periventricular echotexture is abnormally increased (greater than or equal to that of the choroid plexus), which is consistent with the early changes of periventricular leukomalacia (PVL). Courtesy of Matthew Omojola, MD.

Cranial CT scan, axial image, in a 5-week-old premature infant with periventricular leukomalacia (PVL). The ventricular margins are irregular, which is consistent with incorporation of the periventricular cysts of PVL. Mild ventriculomegaly and loss of the periventricular white matter is observed. Courtesy of Matthew Omojola, MD.

Cranial MRI, T1-weighted axial image, in an 18-month-old with periventricular leukomalacia (PVL). The lateral ventricles are enlarged without hydrocephalus. The periventricular white matter is diminished. Courtesy of Matthew Omojola, MD.

Cranial MRI, T2-weighted axial image, in an 18-month-old with periventricular leukomalacia (PVL). Again, enlarged ventricles and loss of white matter are demonstrated. Also noted is the abnormal increased signal in the periventricular regions on this T2-weighted image. Courtesy of Matthew Omojola, MD.

Cranial MRI, sagittal T1-weighted image in the midline, in an 18-month-old with periventricular leukomalacia (PVL). Hypoplasia of the corpus callosum is present and is most evident, involving the body. Courtesy of Matthew Omojola, MD.